ABSTRACT Infertility and spontaneous abortion (SAB) are significant public health problems, affecting up to 25% of reproductive age couples in the United States. Health care costs attributable to infertility and SAB exceed $5 billion per year, and several studies have shown an association between infertility treatments and adverse pregnancy outcomes. Thus, identifying modifiable risk factors for subfertility and SAB is an important public health goal. The potential effects of exposure to endocrine-disrupting chemicals (EDCs) on risk of subfertility and SAB are understudied. The few existing human studies have limitations including small sample size, enrollment after conception, retrospective study design, suboptimal assessment of exposure and outcome, inadequate control for potential confounding variables, and limited generalizability. The proposed study will prospectively assess the relation of exposure to selected EDCs, including phenols, phthalates, and per- and poly-fluoroalkyl substances (PFAS), to risk of subfertility and SAB in a preconception subcohort of 950 pregnancy planners. We will use data from two NICHD-supported prospective cohorts of pregnancy planners in North America and Denmark. With web-based recruitment and data collection, we have enrolled over 17,000 women attempting pregnancy into these cohorts. In a subset of 200 participants, we have successfully pilot tested in-person collection of urine and blood specimens during the preconception and early pregnancy periods. In this application, we propose to expand in-person biospecimen collection, increasing the number of women with preconception and early pregnancy urine and blood samples from 200 to 950. At each of our three biospecimen collection sites (Boston, Detroit, and Aarhus), we will enroll 250 women and collect three urine samples and one blood sample (in preconception) and three urine samples and one blood sample (in early pregnancy). We will ship the samples to the CDC for the analysis of urinary phthalates, urinary phenols, and serum PFAS. To increase cost efficiency, we will pool three urine samples in each exposure window before assaying for phthalates and phenols; and we will assay one preconception blood specimen for PFAS, a persistent chemical, in analyses of subfertility and SAB. Finally, we will conduct a pilot study among 100 U.S. participants to assess the feasibility of collecting urine by mail, which would allow us to take advantage of our full geographically-diverse cohort in the future. Strengths of this application include the prospective design, preconception enrollment of pregnancy planners, repeated measurement of exposure during preconception and early pregnancy, excellent control for confounding via bimonthly prospective data collection on a wide range of covariates, and use of the latest analytic methods for mixtures modeling. We have generated compelling preliminary data to support our aims. The present grant is cost-effective in leveraging already-established cohort studies with data collection and follow-up supported by other grants. The results generated will be translatable by directly informing future regulatory decisions about EDC standards in a manner that could reduce rates of infertility and SAB.